biostudies-literatureAli FRCancer Research UKMBRU College of Medicine InternalWellcome Trust InvestigatorMedical Research CouncilMBRU-ALMAHMEED Collaborative Research AwardMRC ResearchWellcome Trust1759-1766https://www.ebi.ac.uk/biostudies/studies/S-EPMC7614603biostudies-literatureUnknown18(12)Pediatric cancers often resemble trapped developmental intermediate states that fail to engage the normal differentiation program, typified by high-risk neuroblastoma arising from the developing sympathetic nervous system. Neuroblastoma cells resemble arrested neuroblasts trapped by a stable but aberrant epigenetic program controlled by sustained expression of a core transcriptional circuit of developmental regulators in conjunction with elevated MYCN or MYC (<i>MYC</i>). The transcription factor ASCL1 is a key master regulator in neuroblastoma and has oncogenic and tumor-suppressive activities in several other tumor types. Using functional mutational approaches, we find that preventing CDK-dependent phosphorylation of ASCL1 in neuroblastoma cells drives coordinated suppression of the MYC-Molecular cancer research : MCRDephosphorylation of the Proneural Transcription Factor ASCL1 Re-Engages a Latent Post-Mitotic Differentiation Program in Neuroblastoma.PMC7614603212253/Z/18/Z20411212253MBRU-CM-RG2019–14MC_PC_12009MC_PC_17230MR/L021129/1ALM1909RG9150525636Papkovskaia TDChernukhin IParkinson LMWoods LMAli FRDavies JDPhilpott AWylie LACarroll JSMarcos DfalseDephosphorylation of the Proneural Transcription Factor ASCL1 Re-Engages a Latent Post-Mitotic Differentiation Program in Neuroblastoma.Pediatric cancers often resemble trapped developmental intermediate states that fail to engage the normal differentiation program, typified by high-risk neuroblastoma arising from the developing sympathetic nervous system. Neuroblastoma cells resemble arrested neuroblasts trapped by a stable but aberrant epigenetic program controlled by sustained expression of a core transcriptional circuit of developmental regulators in conjunction with elevated MYCN or MYC (<i>MYC</i>). The transcription factor ASCL1 is a key master regulator in neuroblastoma and has oncogenic and tumor-suppressive activities in several other tumor types. Using functional mutational approaches, we find that preventing CDK-dependent phosphorylation of ASCL1 in neuroblastoma cells drives coordinated suppression of the MYC-2020-01-01T00:00:00Z2020 Dec2026-05-28T20:09:26.24Z2025-02-19T04:45:54.367ZS-EPMC76146033304653510.1158/1541-7786.MCR-20-069310.1158/1541-7786.mcr-20-0693